Potentiation of benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis in mice by D,L-buthionine-S,R-sulfoximine-mediated tissue glutathione depletion

In vitro studies have suggested that the glutathione (GSH) S-transferase (G ST)-catalyzed GSH conjugation is an important mechanism for the detoxificat ion of (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE]. which is the activated form of the widespread environmenta l pollutant benzo[a]pyrene (BP). However, in vivo experimental evidence for the importance of GSH/GST system in defense against carcinogenic effects o f BP is lacking. We hypothesized that if GSH/GST were to play an important role in the detoxification of (+)-anti-BPDE, the tumorigenic activity of BP would be increased by depleting the levels of GSH, which is the required n ucleophilic substrate for GST-catalyzed conjugation reactions. In the prese nt study: we have tested the above hypothesis by determining the effect of D,L-buthionine-S,R-sulfoximine (BSO)-mediated tissue GSH depletion on BP-in duced tumorigenesis of the lung and forestomach in female A/J mice. Treatme nt of mice with three i.p. injections of 2.5 mmol BSO/kg (12 h apart) plus 20 mM BSO in drinking water, resulted in a statistically significant reduct ion in hepatic, pulmonary and forestomach GSH levels. At the same time, BSO -administration caused a statistically significant increase in BP-induced p ulmonary and forestomach tumor multiplicity. To the best of our knowledge, the present study is the first report that provides in vivo experimental ev idence for the importance of GSH/GST system in cellular protection against carcinogenic effects of BP. (C) 2000 Elsevier Science Ireland Ltd. All righ ts reserved.